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Current Rheumatology Reports Jun 2016Elevated serum urate concentration is the primary cause of gout. Understanding the processes that affect serum urate concentration is important for understanding the... (Review)
Review
Elevated serum urate concentration is the primary cause of gout. Understanding the processes that affect serum urate concentration is important for understanding the etiology of gout and thereby understanding treatment. Urate handing in the human body is a complex system including three major processes: production, renal elimination, and intestinal elimination. A change in any one of these can affect both the steady-state serum urate concentration as well as other urate processes. The remarkable complexity underlying urate regulation and its maintenance at high levels in humans suggests that this molecule could potentially play an interesting role other than as a mere waste product to be eliminated as rapidly as possible.
Topics: Gout; Humans; Hyperuricemia; Intestinal Mucosa; Kidney; Kidney Tubules; Organic Anion Transporters; Renal Reabsorption; Uric Acid
PubMed: 27105641
DOI: 10.1007/s11926-016-0587-7 -
American Journal of Physiology. Heart... Sep 2019Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a/CD68 M1 macrophages into the renal medulla....
Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a/CD68 M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a/CD68 macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg·day) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a/CD68 macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a immune cells. Cholinergic activation of CD161a immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response. This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension.
Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Hypertension; Inflammation Mediators; Kidney; Macrophages; Male; NK Cell Lectin-Like Receptor Subfamily B; Nicotine; Nicotinic Agonists; Phenol; Rats, Inbred SHR; Renal Artery; Renal Reabsorption; Sodium; Solute Carrier Family 12, Member 1; Sympathectomy, Chemical
PubMed: 31172810
DOI: 10.1152/ajpheart.00234.2019 -
Frontiers in Physiology 2021Euryhaline teleosts exhibit major changes in renal function as they move between freshwater (FW) and seawater (SW) environments, thus tolerating large fluctuations in... (Review)
Review
Euryhaline teleosts exhibit major changes in renal function as they move between freshwater (FW) and seawater (SW) environments, thus tolerating large fluctuations in salinity. In FW, the kidney excretes large volumes of water through high glomerular filtration rates (GFR) and low tubular reabsorption rates, while actively reabsorbing most ions at high rates. The excreted product has a high urine flow rate (UFR) with a dilute composition. In SW, GFR is greatly reduced, and the tubules reabsorb as much water as possible, while actively secreting divalent ions. The excreted product has a low UFR, and is almost isosmotic to the blood plasma, with Mg, SO , and Cl as the major ionic components. Early studies at the organismal level have described these basic patterns, while in the last two decades, studies of regulation at the cell and molecular level have been implemented, though only in a few euryhaline groups (salmonids, eels, tilapias, and fugus). There have been few studies combining the two approaches. The aim of the review is to integrate known aspects of renal physiology (reabsorption and secretion) with more recent advances in molecular water and solute physiology (gene and protein function of transporters). The renal transporters addressed include the subunits of the Na, K- ATPase (NKA) enzyme, monovalent ion transporters for Na, Cl, and K (NKCC1, NKCC2, CLC-K, NCC, ROMK2), water transport pathways [aquaporins (AQP), claudins (CLDN)], and divalent ion transporters for SO , Mg, and Ca (SLC26A6, SLC26A1, SLC13A1, SLC41A1, CNNM2, CNNM3, NCX1, NCX2, PMCA). For each transport category, we address the current understanding at the molecular level, try to synthesize it with classical knowledge of overall renal function, and highlight knowledge gaps. Future research on the kidney of euryhaline fishes should focus on integrating changes in kidney reabsorption and secretion of ions with changes in transporter function at the cellular and molecular level (gene and protein verification) in different regions of the nephrons. An increased focus on the kidney individually and its functional integration with the other osmoregulatory organs (gills, skin and intestine) in maintaining overall homeostasis will have applied relevance for aquaculture.
PubMed: 33967835
DOI: 10.3389/fphys.2021.664588 -
Current Opinion in Nephrology and... Sep 2016The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes... (Review)
Review
PURPOSE OF REVIEW
The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes recent findings of how defects in paracellular chloride permeation pathway may cause kidney diseases and how such a pathway may be regulated to maintain normal chloride homeostasis.
RECENT FINDINGS
The tight junction in the collecting duct expresses two important claudin genes - claudin-4 and claudin-8. Transgenic knockout of either claudin gene causes hypotension, hypochloremia, and metabolic alkalosis in experimental animals. The claudin-4 mediated chloride permeability can be regulated by a protease endogenously expressed by the collecting duct cell - channel-activating protease 1. Channel-activating protease 1 regulates the intercellular interaction of claudin-4 and its membrane stability. Kelch-like 3, previously identified as a causal gene for Gordon's syndrome, also known as pseudohypoaldosteronism II, directly interacts with claudin-8 and regulates its ubiquitination and degradation. The dominant pseudohypoaldosteronism-II mutation (R528H) in Kelch-like 3 abolishes claudin-8 binding, ubiquitination, and degradation.
SUMMARY
The paracellular chloride permeation pathway in the kidney is an important but understudied area in nephrology. It plays vital roles in renal salt handling and regulation of extracellular fluid volume and blood pressure. Two claudin proteins, claudin-4 and claudin-8, contribute to the function of this paracellular pathway. Deletion of either claudin protein from the collecting duct causes renal chloride reabsorption defects and low blood pressure. Claudins can be regulated on posttranslational levels by several mechanisms involving protease and ubiquitin ligase. Deregulation of claudins may cause human hypertension as exemplified in the Gordon's syndrome.
Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Pressure; Carrier Proteins; Chlorides; Claudin-4; Claudins; Humans; Kidney Diseases; Kidney Tubules, Collecting; Microfilament Proteins; Permeability; Pseudohypoaldosteronism; Renal Reabsorption; Serine Endopeptidases; Tight Junctions
PubMed: 27490784
DOI: 10.1097/MNH.0000000000000253 -
Physiological Reports Jul 2018Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg homeostasis. Impaired activity of the Na -Cl...
Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg homeostasis. Impaired activity of the Na -Cl -cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg balance. To further elucidate the possible interrelationship between NCC activity and renal Mg handling, plasma Mg levels and urinary excretion of sodium (Na ) and Mg were measured in a mouse model of Gordon syndrome. In this model, DCT1-specific expression of a constitutively active mutant form of the NCC-phosphorylating kinase, SPAK (CA-SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)-sensitive Na reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg levels in CA-SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA-SPAK mice exhibited greater NCC-dependent Na reabsorption together with decreased Mg reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA-SPAK mice exhibited higher urinary Mg excretion, while urinary Na excretion decreased to levels observed in control animals. Surprisingly, CA-SPAK mice had unaltered renal expression of Trpm6, encoding the Mg -permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA-SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na reabsorption. Thus, Mg reabsorption is not coupled to increased thiazide-sensitive Na reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg excretion after prolonged HCTZ administration.
Topics: Animals; Arthrogryposis; Cation Transport Proteins; Cleft Palate; Clubfoot; Female; Hand Deformities, Congenital; Hydrochlorothiazide; Kidney; Magnesium; Male; Mice; Protein Serine-Threonine Kinases; Renal Reabsorption; Sodium; Sodium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 3; TRPM Cation Channels
PubMed: 30030908
DOI: 10.14814/phy2.13728 -
Clinical Journal of the American... Jul 2014The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to... (Review)
Review
The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology.
Topics: Acid-Base Equilibrium; Animals; Glomerular Filtration Rate; Humans; Hydrogen-Ion Concentration; Nephrons; Phosphates; Potassium; Proteins; Renal Reabsorption; Sodium; Water; Water-Electrolyte Balance
PubMed: 24789550
DOI: 10.2215/CJN.08860813 -
Experimental Physiology Apr 2015What is the topic of this review? The sympathetic control of renal sodium tubular reabsorption is dependent on activation of the intrarenal renin-angiotensin system and... (Review)
Review
What is the topic of this review? The sympathetic control of renal sodium tubular reabsorption is dependent on activation of the intrarenal renin-angiotensin system and activation of the angiotensin II type 1 (AT1 ) receptor by angiotensin II. What advances does it highlight? Despite the fact that the interaction between the sympathetic nervous system and angiotensin II regarding salt reabsorption is a well-known classical mechanism for the maintenance of extracellular volume homeostasis, the underlying molecular signalling is not clearly understood. It has been shown recently that renal nerve stimulation increases intrarenal angiotensin II and activates the AT1 receptor, triggering a signalling cascade that leads to elevations of Na(+) -H(+) exchanger isoform 3-mediated tubular transport. In this short review, the crosstalk between intrarenal angiotensin II and renal nerve activity and its effect on sodium reabsorption is addressed. In this review, we address the importance of the interaction between the sympathetic nervous system and intrarenal renin-angiotensin system in modulating renal tubular handling of sodium and water. We have recently shown that increased Na(+) -H(+) exchanger isoform 3 (NHE3) activity induced by renal nerve stimulation (RNS) depends on the activation of the angiotensin II type 1 (AT1 ) receptor by angiotensin II (Ang II). Low-frequency RNS resulted in higher levels of intrarenal angiotensinogen and Ang II independent of changes in blood pressure, the glomerular filtration rate and systemic angiotensinogen. Angiotensin II, via the AT1 receptor, triggered an intracellular pathway activating NHE3 in the renal cortex, leading to antinatriuresis and antidiuresis. Pharmacological blockade of the AT1 receptor with losartan prior to RNS abolished both the functional and the molecular responses, suggesting that intrarenal Ang II acting via the AT1 receptor is a major factor for NHE3-mediated sodium and water reabsorption induced by RNS.
Topics: Angiotensin II; Animals; Glomerular Filtration Rate; Humans; Kidney; Renin-Angiotensin System; Sodium; Sympathetic Nervous System
PubMed: 25858030
DOI: 10.1113/EP085075 -
International Journal of Molecular... Apr 2024To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This... (Review)
Review
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
Topics: Humans; Phosphates; Animals; Renal Reabsorption; Kidney; Kidney Tubules, Proximal
PubMed: 38731904
DOI: 10.3390/ijms25094684 -
Current Opinion in Toxicology Sep 2022The kidneys are responsible for maintaining physiologic homeostasis. The kidneys clear a variety of drugs and other substances through passive (filtration) and active...
The kidneys are responsible for maintaining physiologic homeostasis. The kidneys clear a variety of drugs and other substances through passive (filtration) and active processes that utilize transport proteins. Renal clearance is comprised of the processes of glomerular filtration, tubular secretion, and tubular reabsorption. Endogenous biomarkers, such as creatinine and cystatin C, are routinely used to estimate renal clearance. Understanding the contributing components of renal function and clearance, through the use of biomarkers, is necessary in elucidating the renal pharmacology of drugs and other substances. While exogenous markers of kidney function have been known for decades, several complexities have limited their usage. Several endogenous markers are being evaluated and hold promise to elucidate the individual components of kidney function that represent filtration, secretion, and reabsorption.
PubMed: 36777447
DOI: 10.1016/j.cotox.2022.03.005 -
IScience Dec 2022Our recent study has found that gut bacteria contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to...
Our recent study has found that gut bacteria contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to investigate the role of LYPLA1 in the development of -induced hypertension. Compared to control, treatment increased blood pressure (BP), serum angiotensin II, sodium reabsorption, and expression of αENaC and LYPLA1 in the renal medulla of mice, and these effects were attenuated by knockdown of LYPLA1. Moreover, the intrarenal overexpression increased sodium reabsorption and BP. Further studies showed that LYPLA1 promoted the accumulation of renal glycerophosphocholine (GPC), which directly elevated the expression of αENaC and sodium reabsorption. In addition, enriched abundance of LYPLA1 in the renal medulla and urine was also observed in other hypertensive animals. Overall, our results demonstrate that LYPLA1 contributes to -induced hypertension by accumulating GPC and activating ENaC in the renal medulla.
PubMed: 36419851
DOI: 10.1016/j.isci.2022.105403